Editorial: Development of novel small molecules as therapeutics for inflammatory diseases and delineating their molecular mechanisms

Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, United States, The University of Texas Health Science Center at Tyler, Tyler, TX, United States, Ben-Gurion University of the Negev, Beersheba, Israel, Department of Biochemistry, School of Biological Sciences, Madurai Kamaraj University Madurai, Madurai, India, Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia, University of Reading, Reading, United Kingdom


Introduction
Inflammation is a critical and rapid physiological response of our immune system to any infection or tissue injury which is associated with various diseases (Zhu and Hou, 2021). However, when the inflammatory response fails to resolve the cause of inflammation, it can be detrimental and lead to the development of many diseases (Hanke et al., 2016;Ramprasath et al., 2021). Though, currently many approved antiinflammatory drugs are in clinical use (e.g., non-steroidal anti-inflammatory drugs; NSAIDs), (Kohler et al., 2016), the long-term use of anti-inflammatory drugs are associated with many side effects including, gastrointestinal reactions and damages to the cardiovascular system (Wongrakpanich et al., 2018). In medicinal chemistry, the discovery based on the small molecule approach has opened the door to a new way to develop novel therapeutics for people with severe inflammatory conditions. In recognition of the clinical value of this study, this subject featured fourteen original research and two The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Frontiers in Pharmacology frontiersin.org 01 review articles in the field of inflammation and small molecule study with a larger perspective to generate ideas for future scientific and clinical research.

Small molecule inhibitors targeting the NLRP3 inflammasome
NF-κB is a key activator of inflammation that primes the NLR pyrin domain 3 (NLRP3)-inflammasome for its activation (Zhong et al., 2016). In this special issue, different research groups published their work focused mainly on inflammasome. Zhao et al. investigated a compound named FxUD, which suppressed the NF-κB/ NLRP3 signaling pathway and lowered the serum uric acid level to alleviate renal inflammation in hyperuricemic mice. Similarly, another compound KPT-8602, was validated for its potential to inhibit the activation of the NF-κB/NLRP3 signaling.

Small molecule modulators for COVID-19
Trichomicin, a novel small-molecule compound, is isolated from the fungus Trichoderma harzianum (Zhu et al., 2020). Trichomicin was explored for its inhibitory effect on cytokine expression by Chen et al. This compound could inhibit the Stat3 and NF-κB phosphorylation and showed the potential to treat the patients with cytokine release syndrome, a significant cause of COVID-19 disease severity. Vascular inflammation is one of the unusual symptoms among COVID-19 survivors. Ragavan et al. showed that histamine and histamine receptor signaling is likely to be essential for SARS-CoV-2 spike protein S1 Receptor-Binding Domain (Spike) protein to induce ACE2 internalization in endothelial cells, which causes endothelial dysfunction. This effect was blocked by treating with famotidine (a histamine H2 receptor blocker), an antiviral drug (Mukherjee et al., 2021), in cultured human coronary artery endothelial cells.

Small molecule inhibitors for inflammatory diseases
ACT-1004-1239 is a compound that showed a therapeutic effect against LPS inhalation-induced lung vascular injury in vivo. The authors provided data to show that this compound can alleviate acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) (Pouzol et al.). Similarly, another compound, M20 interact with the MyD88-Toll/interleukin-1 receptor domain and thereby inhibits the protein dimerization, which could serve as a potential strategy for the treatment of acute lung injury (

Conclusion and future perspective
Small molecules offer numerous advantages compared to currently used biological therapies. Identifying small molecules Frontiers in Pharmacology frontiersin.org 02 with shorter half-lives helps the patients stop taking their medication quickly, which could offer better medical management. Hence, employing advanced and novel approaches in the development of small molecule therapeutics is urgently needed. We hope that the scientific knowledge provided in this special issue will encourage many researchers to address the several outstanding challenges in this field to advance scientific research on inflammatory signaling events and small molecule interactions to promote better therapeutic development.

Author contributions
All the authors contributed equally to the editing and writing of this article. Furthermore, all authors approved the final version of this article.